The role of antigen-presenting cells (APC) in regulating the balance of T helper type 1 (Th1) and T helper 2 (Th2) responses and cytokine production is unclear. Dendritic cells (DC), the most potent APC for naive T cell activation, were found to regulate Th1 and Th2 cytokine profiles in a manner dependent on their tissue of origin. Using whole tissues or purified cell mixtures, spleen (systemic) DC were found to induce mainly Th1 cytokines, and Peyer's patch (mucosal) DC were found to induce predominantly Th2 cytokines. Spleen DC induced high levels of interferon-γ (IFN-γ) or interleukin-2 (IL- 2) or both, and Peyer's patch DC induced IL-4 or IL-6 or both in spleen and Peyer's patch T cells, allogeneic mixed leukocyte reactions, or antigen- specific Th0 clones. These data suggest that the tissue of origin of DC has a significant impact on subsequent T cell development.